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Vol. 63, Issue 1, 2-8, January 2003
Institute of Medical Science (J.Y.T.Y., B.A.O.) and Departments of Anesthesia (K.J.C., B.A.O.), Physiology (G.Z., J.F.M, B.A.O.), and Pharmaceutical Sciences (P.P, J.F.M.), University of Toronto, Toronto, Ontario, Canada; and Department of Anesthesia, Sunnybrook and Women's College Health Science Center, Toronto, Ontario, Canada (B.A.O.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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In the hippocampus, two distinct forms of GABAergic inhibition
have been identified, phasic inhibitory postsynaptic currents that are
the consequence of the vesicular release of GABA and a tonic
conductance that is activated by low ambient concentrations of
extracellular GABA. It is not known what accounts for the distinct properties of receptors that mediate the phasic and tonic inhibitory conductances. Moreover, the physiological role of the tonic inhibitory conductance remains uncertain because pharmacological tools that clearly distinguish tonic and phasic receptors are lacking. Here, we
demonstrate that GABAA receptors that generate a tonic
conductance in cultured hippocampal neurons from embryonic mice have
different pharmacological properties than those in cerebellar granule
neurons or pyramidal neurons in the dentate gyrus. The tonic
conductance in cultured hippocampal neurons is enhanced by the
benzodiazepine, midazolam, and is insensitive to the inhibitory effects
of the competitive antagonist, gabazine (
10 µM). We also identify
penicillin as an uncompetitive antagonist that selectively inhibits the
synaptic but not tonic conductance. GABA was applied to hippocampal
neurons to investigate the properties of synaptic and extrasynaptic
receptors. GABA-evoked current was composed of two components: a
rapidly desensitizing current that was blocked by penicillin and a
nondesensitizing current that was insensitive to penicillin blockade.
The potency of GABA was greater for the penicillin-insensitive
nondesensitizing current. Single-channel studies show that the
gabazine-insensitive GABAA receptors have a lower unitary
conductance (12 pS) than that estimated for synaptic receptors. Thus,
specialized GABAA receptors with an apparent higher
affinity for GABA that do not readily desensitize mediate the
persistent tonic conductance in hippocampal neurons. The receptors
underlying tonic and phasic inhibitory conductances in hippocampal
neurons are pharmacologically and biophysically distinct, suggesting
that they serve different physiological roles.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The
inhibitory neurotransmitter GABA is thought to regulate point-to-point
communication between neurons by activating GABAA receptors clustered in postsynaptic densities. However, GABA also serves a "paracrine" function by diffusing away from the synaptic cleft and activating extrasynaptic GABAA and
GABAB receptors that reside beyond subsynaptic
domains (for review, see Isaacson, 2000
; Mody, 2001). Ambient GABA can
also arise by the reverse operation of GABA cotransporters in neurons
and astrocytes (Liu et al., 2000; Wu et al., 2001). Thus,
GABAA receptors need not be restricted to
synapses to serve physiological functions. Moreover,
GABAA receptors responsible for the tonic
inhibitory conductance in some brain regions may be of clinical
importance as targets for anesthetics and sedative drugs (Bai et al.,
2001). Abnormal regulation of the tonic conductance may also play a
role in hyperexcitatory disorders such as epilepsy. Anticonvulsants
that increase the extracellular concentration of GABA may primarily
increase the tonic inhibitory conductance (Overstreet and Westbrook,
2001). Despite their probable importance, the physiological role of
tonic GABAA receptors in specific brain regions,
including the hippocampus, remains to be elucidated.
At least 19 different GABAA subunits that confer
distinct pharmacological and biophysical properties have been
identified (Rudolph et al., 2001). Subunit composition influences
agonist affinity, receptor kinetics, and segregation of receptors to
subcellular regions of the neuron (Nusser et al., 1998). For example,
extrasynaptic GABAA receptors in cerebellar
granule neurons contain 
6 and 
subunits.
The properties of native and recombinant GABAA
receptors suggest that these subunits confer a high affinity for GABA,
low single-channel conductance, and slow kinetics of desensitization (Saxena and Macdonald, 1994; Brickley et al., 1999; Haas and Macdonald, 1999; Mellor et al., 2000). Receptors containing subunits may also
underlie a benzodiazepine-insensitive tonic conductance in dentate
granule neurons (Nusser and Mody, 2002). Tonic inhibitory conductances
have also been identified in the thalamus, the CA1 hippocampal region,
and the cortex (Valeyev et al., 1998; Liu et al., 2000; Bai et al.,
2001). However, the subunit composition and the pharmacological
characteristics of GABAA receptors responsible for the tonic GABAergic conductance (referred to here as tonic receptors) remain to be elucidated in these brain regions.
We first showed that the tonic and synaptic conductances in embryonic
hippocampal neurons displayed different sensitivities to the
high-affinity competitive antagonist gabazine (SR-95531) (Bai et al.,
2001). Also, noise analysis indicated the tonic receptors have a lower
unitary channel conductance (7 pS) than that reported for
synaptic receptors (25 pS). Here, we further characterized the
properties of the tonic and synaptic (phasic) receptors in hippocampal
neurons and identified penicillin-G as a selective antagonist of phasic
receptors. Single-channel studies provided evidence that
low-conductance, high-affinity channels mediated the tonic conductance.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Cell Culture and Electrophysiological Techniques.
Cultures
of hippocampal neurons were prepared from embryonic Swiss White mice as
described previously (MacDonald et al., 1989). Conventional
whole-cell currents were recorded under voltage-clamp (
60 mV) using
an Axopatch 200 amplifier (Axon Instruments Inc., Union City, CA) that
was interfaced to a Digidata 1200 (Instrutech Corp., Elmont, NY).
Records were filtered (2 kHz) and digitized at 10 kHz using pClamp6
software (Axon Instruments Inc.) for off-line analyses.
Data Analysis.
Spontaneous mIPSCs were analyzed using
MiniAnalysis Software (Synaptosoft, Leonia, NJ) with the detection
threshold set three times higher than the level of baseline noise. The
peak amplitude, charge transfer (Q, determined by integrating the area
under the mIPSCs), and time constant of current decay
(
decay) were analyzed. The
decay was determined using the biexponential
equation, I(t) = A1exp
(t/1) + A2exp
(t/2), where I is the
current amplitude at any given time (t),
A1 and
A2 are the amplitudes of the fast and
slow decay components, and 1 and
2 are their respective decay time constants.
The weighted time constant of current decay was determined by the
equation decay = 
Aii/Ai.
; Wall and Usowicz, 1997). The holding
current was analyzed using 15 100-ms segments that lacked mIPSCs. The
segments were acquired before and after drug treatment. All-point
histograms were constructed from these segments and mean values were
determined from Gaussian fits (pStat; Axon Instruments Inc.). The
root-mean-square noise (
) was calculated from segments that lacked
mIPSCs using Mini Analysis software (Synaptosoft) according to the
equation = 
Single Channel Analysis.
Outside-out patches were excised
from the somata and voltage clamped at 70 mV. Recordings were
low-pass-filtered at 1 kHz (3 dB, 8-pole Bessle), digitized at 20 kHz, and recorded on videotape for off-line analysis. To estimate the
amplitude of the various conductance levels, we first constructed
all-point histograms. The current-voltage relationships of the various
conductance levels were also analyzed using the all-point histograms.
Amplitude and all-point histograms were fitted with the sum of several
Gaussian components using a Levenberg-Marguardt least-squares
minimization (pStat; Axon Instruments Inc.). The frequency of channel
opening was determined using the threshold crossing method. High-,
mid-, and low-conductance openings that crossed the 50% threshold
level were selected and the minimal open duration was set at 200 µs.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Tonic and Synaptic GABAA Receptors Are
Pharmacologically Distinct.
Two distinct types of current were
evident in whole-cell recordings, including phasic mIPSCs and a
persistent tonic current that was revealed by the application of the
GABAA receptor antagonist, bicuculline (Fig.
1A). The mIPSCs had a frequency of
2.1 ± 0.7 Hz, a rise time of 2.8 ± 0.3 ms, an amplitude of
27.2 ± 2.6 pA (n = 6), and a decay that was best
described by a biexponential equation with a weighted time constant
(tdecay) of 19.3 ± 2.9 ms.
Bicuculline (10 µM) abolished the mIPSCs and produced an outward shift in the baseline by 18.4 ± 1.3 pA (n = 39).
Higher concentrations of bicuculline (100 µM) caused no further shift
in the holding current. The tonic conductance was mediated by
GABAA receptors as the current reversed polarity
at the chloride equilibrium potential and was blocked by other
GABAA receptor antagonists (Bai et al., 2001).
Bicuculline (10 µM) also reduced the baseline noise as indicated by a
reduction in the root-mean-square value () from 4.2 ± 0.2 to
2.9 ± 0.1 pA, (n = 39, p < 0.05). The ratio of the variance/mean tonic current
([2+tonic 2tonic]/Itonic)
predicted the unitary conductance of the underlying tonic receptors to
be 8 pS. This value is smaller than the full conductance state
estimated for synaptic receptors (25 pS; De Koninck and Mody, 1994) but
similar to the low-conductance state observed in the single-channel
studies described below.
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10 µM) abolished the mIPSCs
but failed to reduce the amplitude of the tonic current (1.1 ± 2.9 pA, n = 16), as we reported previously (Bai et al., 2001). This apparent insensitivity to gabazine could result from a
higher affinity of the tonic receptors for GABA (Stell and Mody, 2002)
or from the greater potency of gabazine for synaptic receptors. Indeed,
higher concentrations of gabazine (
100 µM) reduced the holding
current (6.3 ± 10.0 pA, n = 6) and the (3.9 ± 0.5 to 2.9 ± 0.2 pA, n = 6)
indicating that gabazine modulates tonic receptor function.
Furthermore, although gabazine is considered to be a competitive
antagonist, it also allosterically regulates GABAA receptor activity (Ueno et al., 1997). We
previously proposed that gabazine may act as a partial agonist at the
GABAA receptors in embryonic hippocampal neurons
to activate a small residual conductance (Bai et al., 2001). Consistent
with this prediction, in three recordings, gabazine (100 µM) caused a
small inward current (13.5 ± 5.4 pA) that was blocked by
bicuculline (10 µM). Thus, gabazine blocked synaptic receptors but
also enhanced the tonic current, making it a less than an ideal tool
for probing the physiological roles of the tonic conductance.
Selective Blockade of Synaptic Receptors by Penicillin.
In a
continued search for compounds that distinguish between tonic and
phasic conductances, we examined the effects of the noncompetitive
antagonists picrotoxin,
tert-butyl-bicyclo[2.2.2]phosphorothionate (TBPS), and
penicillin-G (penicillin). Rather than compete at the GABA recognition
site, these antagonists block the receptor by binding to sites within
or near the open channel pore. TBPS (10 µM) and picrotoxin (100 µM)
abolished the mIPSCs and blocked the tonic current as evidenced by the
outward shift of the baseline (15.0 ± 2.3 pA, n = 4, and 19.2 ± 4.9 pA, n = 4, respectively; Fig.
1B). In contrast, penicillin (0.1 to 20 mM) caused a
concentration-dependent inhibition of the synaptic currents but failed
to block the tonic current (Fig. 1C). Although the amplitude of the
tonic current was unchanged by penicillin (5 mM; 1.3 ± 0.7 pA,
n = 25), was slightly reduced (3.9 ± 0.3 to
3.1 ± 0.2 pA; p < 0.05). Higher concentrations
of penicillin (20 mM) had no additional action on the amplitude of the
tonic current (3.2 ± 1.5 pA, n = 6, p > 0.05); however, it further reduced (4.4 ± 0.8 to 3.2 ± 0.4 pA, p < 0.05). These results
suggest that although penicillin did not block the tonic current, it
nevertheless influences the tonic receptors. This action is expected
for an uncompetitive blocker that fails to block responses generated
under conditions of low receptor occupancy (Pennefather and Quastel,
1982).
Enhanced Tonic Receptor Function and Penicillin Blockade.
Activation of the GABAA receptor facilitates
inhibition by use-dependent antagonists that require channel opening to
reach their site of blockade. Thus, the relative insensitivity of tonic receptors to penicillin could result from a low probability of channel
opening. Two strategies were used to determine whether an increase in
channel opening influenced the penicillin sensitivity of the tonic
receptors. First, the benzodiazepine midazolam was applied to
allosterically enhance GABAA receptor activity.
Midazolam (0.2 µM) increased the amplitude of the tonic current by
3.5-fold (64.2 ± 18 pA, n = 3, p < 0.05; Fig. 2B). Despite this
enhancement, penicillin (5 mM, 1.4 ± 1.8 pA, n = 4; Fig. 2B) and gabazine (1 µM, 2.2 ± 1.6 pA, n = 3; Fig. 2B) failed to reduce the tonic current. Next, to increase the
ambient concentration of GABA, the degradation of GABA by
GABA-transaminase was inhibited by the GABA-transaminase antagonist
vigabatrin (Engel et al., 2001). Cultures were treated with vigabatrin
(100 µM) for various time intervals (2 h to 3 days) then washed
before the recordings.
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was unchanged (4.5 ± 1.0 pA, n = 9, p > 0.05). After 1 to 3 days, the tonic current was
increased by 142% (48.1 ± 10.0 pA, n = 11 versus
19.9 ± 2.3 pA in control cultures, n = 10, p < 0.05) and the noise increased proportionally
(6.1 ± 1.9 pA, p < 0.05, n = 11;
control 4.6 ± 0.9 pA, n = 10, p < 0.05). The variance/mean tonic current ratio predicted a channel
conductance of 9.4 pS, supporting the hypothesis that low-conductance
channels generate the tonic current.
Despite an increase in the tonic current after vigabatrin (2-8 h), the
amplitude, time course, and frequency of mIPSCs were unchanged:
30.9 ± 1.5 pA, n = 4, control, 27.2 ± 2.6 pA; n = 6; 10-to-90% rise time, 2.5 ± 0.1 ms;
control, 2.8 ± 0.3 ms; and decay,
18.8 ± 1.9 versus 19.3 ± 2.9 ms, respectively. Thus,
factors that regulate GABA metabolism influenced the tonic and synaptic currents differently. After the prolonged treatment (1-3 days), the
amplitude of mIPSCs was increased 49% (n = 6, p < 0.05), whereas the frequency, rise time, and decay
were unchanged: 1.5 ± 0.5 Hz; 10-to-90% rise time, 2.4 ± 0.3 ms; decay, 19.1 ± 1.0 ms, n = 6 (Fig. 2D). These results are consistent with a
report indicating a long-term application (4 days) of vigabatrin
increased the amplitude of mIPSCs in rat hippocampal slices (Engel et
al., 2001). They also suggest that the content of GABAergic vesicles is
increased after a reduction in GABA breakdown (Loscher et al., 1986).
The rise in cytosolic concentration of GABA may also enhance the
reverse operation of GABA transporters, leading to an increase in
ambient GABA.
Despite the enhancement by vigabatrin, the tonic conductance remained
insensitive to penicillin blockade (Fig. 2C). Penicillin (5 mM)
abolished the mIPSCs but failed to reduce the tonic current (2-8 h,
2.2 ± 5.9 pA, n = 5; 1-3 days, 2.3 ± 2.1 pA, n = 5 versus control, 3.4 ± 1.7 pA,
n = 6). Similarly, gabazine (1 µM) failed to block
the tonic current after the 2- to 8-h treatment (1.1 ± 2.5 pA,
n = 8; 2 to 8 h, 0.0 ± 2.3 pA,
n = 5). In cells treated for 1 to 3 days, gabazine
reduced the tonic current to control levels (26.0 ± 10.6 pA,
p < 0.05, n = 7). This effect is
expected if gabazine displaces GABA and acts as a partial agonist.
Together, the above findings show that the tonic receptor is relatively insensitive to penicillin blockade despite an increase in channel opening.
GABA-Evoked Current Reveals Two Populations.
If cultured
hippocampal neurons contain two distinct populations of
GABAA receptors (tonic
penicillin-insensitive and phasic penicillin-sensitive receptors), then it is predicted that
exogenous GABA would generate currents composed of two components.
Also, at least two previous reports suggest that synaptic receptors mediate the fast component of GABA-evoked current, whereas
extrasynaptic receptors mediate the slow deactivating and desensitizing
component (Bai et al., 1999; Banks and Pearce, 2000).
9.5 ± 2.6%, n = 9; Fig. 3, A
and B). In some recordings in which mIPSCs were seen superimposed on
the GABA-evoked current, penicillin abolished the mIPSCs but failed to
reduce the steady-state current (Fig. 3A, inset). Penicillin also
failed to inhibit the nondesensitizing current evoked by a low
concentration of GABA (1 µM).
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Low Conductance Tonic Receptors.
Information about the
conductance of tonic receptors has been limited to estimates obtained
from noise analysis. In a previous study, we showed the tonic receptors
in hippocampal neurons had a lower conductance than that estimated from
nonstationary fluctuation analysis of synaptic receptors (Bai et al.,
2001). To investigate the unitary conductance of tonic receptors, we
recorded single-channel activity from outside-out patches excised from
the somata. GABA (0.5-2 µM) activated bicuculline-sensitive (2 µM)
channel openings that displayed at least three discrete conductance
levels. The chord conductance values of the high-, mid-, and
low-conductance levels were 28.7 ± 0.5 pS, 20.7 ± 0.5 pS,
and 12.3 ± 0.4 pS, respectively (n = 14; Fig.
4A). The three open levels did not
require low concentrations of GABA because they were also evident in
patches exposed to 50 µM GABA (29.4 ± 0.4, 21.7 ± 0.3, and 13.9 ± 0.4 pS, n = 7).
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).
Two approaches were used to analyze channel openings before and after
gabazine (2 µM). First, Popen was
determined by analyzing the relative areas of the all-point histograms.
Next, the relative frequency of channel opening was measured by
counting the number of events at each open level (Fig. 4B2). Both methods yielded qualitatively similar
results. Gabazine (2 µM) changed the open probability of the 29.3-, 20.4-, and 12.3-pS channels by 26 ± 6.4, 40 ± 7.9, and
125 ± 14% (n = 6, p < 0.05) of
control values, respectively. It was not possible to determine whether
the increase in Popen of the low
conductance level by gabazine resulted from the "unmasking" of
previously obscured low-conductance openings or from a shift in opening
to a low subconductance state. An analysis of the frequency of channel
levels (Fig. 4B2) confirmed the relative
insensitivity of the low-conductance openings to blockade by gabazine.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Selective Inhibition by Penicillin and Gabazine.
Herein, we confirm that the tonic and synaptic conductances in
embryonic hippocampal neurons have different sensitivities to gabazine
(10 µM). This finding contrasts the nonselective inhibition by
gabazine (10 µM) of tonic and synaptic conductances in cerebellar granule neurons and dentate gyrus (Brickley et al., 2001; Hamann et
al., 2002; Stell and Mody, 2002). The tonic conductance in cultured
hippocampal neurons also differs from that in the dentate gyrus and the
cerebellum in that it is sensitive to benzodiazepines, which implies
that the underlying receptors in cultured hippocampal neurons contain
subunits but lack subunits.
). Another study also showed that
GABA-evoked current in cultured hippocampal neurons was composed of
rapidly and slowly desensitizing components (Bai et al., 1999). The
pharmacological properties of the slowly desensitizing current differ
from those of synaptic currents, suggesting that they are mediated by
extrasynaptic receptors. Based on these studies, we predicted and
observed that exogenous GABA would activate a low-affinity peak current
that rapidly desensitized (putatively mediated by synaptic receptors) and a more slowly decaying, high-affinity component that did not desensitize (putatively mediated by extrasynaptic receptors). Furthermore, penicillin would preferentially block the peak but not
steady-state current.
Distinct Subunit Composition or State-Dependent Differences in a
Single Receptor Population.
The critical question remains: do the
different pharmacological properties of tonic and synaptic
GABAA conductances in hippocampal neurons
represent two receptor populations with unique subunit structures, are
they merely state-dependent changes in a single population, or some
combination of these two possibilities? Several lines of evidence
suggest that the tonic and synaptic receptors in cultured neurons
have different molecular structures. Our results indicate that
penicillin caused a leftward shift in the GABA concentration-response plot. This finding contrasts reports that showed penicillin failed to
increase the potency of GABA for recombinant
GABAA receptors and native receptors in the rat
frontal cortex (Sugimoto et al., 2002). It should also be noted,
however, that an uncompetitive antagonist can cause a leftward shift in
the concentration-response relationship, even for a single population
of receptors (Pennefather and Quastel, 1982). However, an uncompetitive
mechanism of blockade cannot fully account for our findings because the
peak and steady-state currents were not influenced to the same extent.
Furthermore, these results do not rule out the possibility that
gabazine and penicillin preferentially blocked a high conductance state
of the GABAA receptor.
). Consistent with a difference in the molecular structure, receptors with distinct molecular structures that mediate the tonic conductance in cerebellar granule neurons have a lower single-channel conductance compared with synaptic
receptors (Brickley et al., 1999; Leao et al., 2000). Also, studies of
recombinant subunits and native receptors indicate that
2-deficient receptors display a low channel
conductance (Moss et al., 1990; Angelotti et al., 1992; Lorez et al.,
2000). Alternatively, the multiple open levels of
GABAA receptors in cultured hippocampal neurons
may correspond to differentially liganded states associated with
different conductance levels. Indeed, substrate-dependent gating was
reported for GABAA receptors (Birnir et al.,
2001), as was shown for glutamate-gate
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid channels, in
which single-channel conductance depends on the concentration of
agonist (Smith and Howe, 2000). GABAA receptors have multiple binding sites for agonist, each with a different affinity
for GABA. Channel conductance and sensitivity to antagonists may depend
on the number of GABA binding sites occupied. For example, the
low-conductance GABAA channel openings that were
insensitive to gabazine blockade may represent a mono-liganded form of
the channel.
The efficacy of GABA acting on receptors located at distances away from
the presynaptic terminal would be enhanced if extrasynaptic receptors
had a high affinity for GABA and desensitized slowly. This study
demonstrates that specialized GABAA receptors
with an apparent higher affinity for GABA that do not readily
desensitize mediate the persistent tonic conductance in hippocampal
neurons. Single-channel studies indicate that the concentration of
ambient GABA (0.2-0.8 µM) in the brain is sufficient to activate
low-conductance, gabazine-insensitive tonic receptors (Lerma et al.,
1986). Penicillin failed to block both the tonic conductance and the
nondesensitizing current activated by exogenous GABA, suggesting that
the tonic receptors represent a subpopulation that fails to
desensitize. It should be possible to exploit the differential effects
of penicillin on tonic and phasic conductances to test the hypotheses
that extrasynaptic and synaptic receptors in hippocampal neurons serve
different physiological purposes and that they are structurally distinct.
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Acknowledgments |
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We thank Drs. Michael F. Jackson and Yaël Perez for their review of this manuscript. We also thank Lidia Brandes and Ella Czerwinska for technical support.
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Footnotes |
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Received August 12, 2002; Accepted October 9, 2002
This work was supported by the Ontario Ministry of Health, Epilepsy Canada, Canadian Institutes of Health Research, and Natural Sciences and Engineering Research Council of Canada.
Address correspondence to: Dr. B.A. Orser, Department of Physiology, Medical Science Building, Room 3318, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S-1A8, Canada. E-mail: beverley.orser{at}utoronto.ca
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Abbreviations |
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mIPSC, miniature inhibitory postsynaptic current; GBZ, gabazine; BIC, bicuculline; PEN, penicillin-G; VGB, vigabatrin; TBPS, tert-butyl-bicyclo[2.2.2]phosphorothionate; MIDZ, midazolam.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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6 GABAA receptor subunit.
Brain Res Mol Brain Res
16:
173-178[Medline].-aminobutyric acidA receptors in hippocampal neurons.
Mol Pharmacol
59:
814-8242 and subtypes confer unique kinetic properties on recombinant GABAA receptor currents in mouse fibroblasts.
J Physiol (Lond)
514:
27-45
channels by astrocyte-derived GABA in cultured embryonic rat hippocampal neurons.
J Neurophysiol
84:
1392-14032 subunit.
J Physiol
527 Pt 1:
11-316 subunit.
Neuropharmacology
39:
1495-1513[CrossRef][Medline]. subunit.
J Neurosci
14:
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A. A. Ghavanini, D. A. Mathers, H.-S. Kim, and E. Puil Distinctive Glycinergic Currents With Fast and Slow Kinetics in Thalamus J Neurophysiol, June 1, 2006; 95(6): 3438 - 3448. [Abstract] [Full Text] [PDF]
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V. Y. Cheng, L. J. Martin, E. M. Elliott, J. H. Kim, H. T. J. Mount, F. A. Taverna, J. C. Roder, J. F. MacDonald, A. Bhambri, N. Collinson, et al. Alpha5GABAA receptors mediate the amnestic but not sedative-hypnotic effects of the general anesthetic etomidate. J. Neurosci., April 5, 2006; 26(14): 3713 - 3720. [Abstract] [Full Text] [PDF]
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 Z. Mtchedlishvili and J. Kapur High-Affinity, Slowly Desensitizing GABAA Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells Mol. Pharmacol., February 1, 2006; 69(2): 564 - 575. [Abstract] [Full Text] [PDF]
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F. Jia, L. Pignataro, C. M. Schofield, M. Yue, N. L. Harrison, and P. A. Goldstein An Extrasynaptic GABAA Receptor Mediates Tonic Inhibition in Thalamic VB Neurons J Neurophysiol, December 1, 2005; 94(6): 4491 - 4501. [Abstract] [Full Text] [PDF]
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A. Scimemi, A. Semyanov, G. Sperk, D. M. Kullmann, and M. C. Walker Multiple and Plastic Receptors Mediate Tonic GABAA Receptor Currents in the Hippocampus J. Neurosci., October 26, 2005; 25(43): 10016 - 10024. [Abstract] [Full Text] [PDF]
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S. Keros and J. J. Hablitz Subtype-Specific GABA Transporter Antagonists Synergistically Modulate Phasic and Tonic GABAA Conductances in Rat Neocortex J Neurophysiol, September 1, 2005; 94(3): 2073 - 2085. [Abstract] [Full Text] [PDF]
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N. E. Hallworth and M. D. Bevan Globus Pallidus Neurons Dynamically Regulate the Activity Pattern of Subthalamic Nucleus Neurons through the Frequency-Dependent Activation of Postsynaptic GABAA and GABAB Receptors J. Neurosci., July 6, 2005; 25(27): 6304 - 6315. [Abstract] [Full Text] [PDF]
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 M. A. Haxhiu, P. Kc, C. T. Moore, S. S. Acquah, C. G. Wilson, S. I. Zaidi, V. J. Massari, and D. G. Ferguson Brain stem excitatory and inhibitory signaling pathways regulating bronchoconstrictive responses J Appl Physiol, June 1, 2005; 98(6): 1961 - 1982. [Abstract] [Full Text] [PDF]
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 M. Perouansky, M. I. Banks, and R. A. Pearce The Differential Effects of the Nonimmobilizer 1,2-Dichlorohexafluorocyclobutane (F6, 2N) and Isoflurane on Extrasynaptic Gamma-Aminobutyric AcidA Receptors Anesth. Analg., June 1, 2005; 100(6): 1667 - 1673. [Abstract] [Full Text] [PDF]
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S. S Smith and Q. H. Gong Neurosteroid administration and withdrawal alter GABAA receptor kinetics in CA1 hippocampus of female rats J. Physiol., April 15, 2005; 564(2): 421 - 436. [Abstract] [Full Text] [PDF]
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P. S. Mangan, C. Sun, M. Carpenter, H. P. Goodkin, W. Sieghart, and J. Kapur Cultured Hippocampal Pyramidal Neurons Express Two Kinds of GABAA Receptors Mol. Pharmacol., March 1, 2005; 67(3): 775 - 788. [Abstract] [Full Text] [PDF]
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I. Mody Aspects of the homeostaic plasticity of GABAA receptor-mediated inhibition J. Physiol., January 1, 2005; 562(1): 37 - 46. [Abstract] [Full Text] [PDF]
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 E. M. Petrini, I. Marchionni, P. Zacchi, W. Sieghart, and E. Cherubini Clustering of Extrasynaptic GABAA Receptors Modulates Tonic Inhibition in Cultured Hippocampal Neurons J. Biol. Chem., October 29, 2004; 279(44): 45833 - 45843. [Abstract] [Full Text] [PDF]
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J.-H. Ye, F. Wang, K. Krnjevic, W. Wang, Z.-G. Xiong, and J. Zhang Presynaptic Glycine Receptors on GABAergic Terminals Facilitate Discharge of Dopaminergic Neurons in Ventral Tegmental Area J. Neurosci., October 13, 2004; 24(41): 8961 - 8974. [Abstract] [Full Text] [PDF]
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V. B. Caraiscos, J. G. Newell, K. E. You-Ten, E. M. Elliott, T. W. Rosahl, K. A. Wafford, J. F. MacDonald, and B. A. Orser Selective Enhancement of Tonic GABAergic Inhibition in Murine Hippocampal Neurons by Low Concentrations of the Volatile Anesthetic Isoflurane J. Neurosci., September 29, 2004; 24(39): 8454 - 8458. [Abstract] [Full Text] [PDF]
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M. C. Bieda and M. B. MacIver Major Role For Tonic GABAA Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability J Neurophysiol, September 1, 2004; 92(3): 1658 - 1667. [Abstract] [Full Text] [PDF]
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 J. Liang, E. Cagetti, R. W. Olsen, and I. Spigelman Altered Pharmacology of Synaptic and Extrasynaptic GABAA Receptors on CA1 Hippocampal Neurons Is Consistent with Subunit Changes in a Model of Alcohol Withdrawal and Dependence J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1234 - 1245. [Abstract] [Full Text] [PDF]
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G. Akk, J. Bracamontes, and J. H. Steinbach Activation of GABAA receptors containing the {alpha}4 subunit by GABA and pentobarbital J. Physiol., April 15, 2004; 556(2): 387 - 399. [Abstract] [Full Text] [PDF]
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N. J. Allen, D. J. Rossi, and D. Attwell Sequential Release of GABA by Exocytosis and Reversed Uptake Leads to Neuronal Swelling in Simulated Ischemia of Hippocampal Slices J. Neurosci., April 14, 2004; 24(15): 3837 - 3849. [Abstract] [Full Text] [PDF]
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V. B. Caraiscos, E. M. Elliott, K. E. You-Ten, V. Y. Cheng, D. Belelli, J. G. Newell, M. F. Jackson, J. J. Lambert, T. W. Rosahl, K. A. Wafford, et al. Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by {alpha}5 subunit-containing {gamma}-aminobutyric acid type A receptors PNAS, March 9, 2004; 101(10): 3662 - 3667. [Abstract] [Full Text] [PDF]
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D. Belelli and M. B. Herd The Contraceptive Agent Provera Enhances GABAA Receptor-Mediated Inhibitory Neurotransmission in the Rat Hippocampus: Evidence for Endogenous Neurosteroids? J. Neurosci., November 5, 2003; 23(31): 10013 - 10020. [Abstract] [Full Text] [PDF]
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G. B. Richerson and Y. Wu Dynamic Equilibrium of Neurotransmitter Transporters: Not Just for Reuptake Anymore J Neurophysiol, September 1, 2003; 90(3): 1363 - 1374. [Abstract] [Full Text] [PDF]
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R. E. Egli and D. G. Winder Dorsal and Ventral Distribution of Excitable and Synaptic Properties of Neurons of the Bed Nucleus of the Stria Terminalis J Neurophysiol, July 1, 2003; 90(1): 405 - 414. [Abstract] [Full Text] [PDF]
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E. M. Petrini, P. Zacchi, A. Barberis, J. W. Mozrzymas, and E. Cherubini Declusterization of GABAA Receptors Affects the Kinetic Properties of GABAergic Currents in Cultured Hippocampal Neurons J. Biol. Chem., April 25, 2003; 278(18): 16271 - 16279. [Abstract] [Full Text] [PDF]
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